Project Summary: Abnormal calcium handling such as calcium overload is associated with a variety of cardiac diseases including heart failure and arrhythmia. Our results from preliminary experiments using a pharmaceutical approach, showed that the sigma 1 receptor (Sigma-1R) is a new therapeutic target for the cardiac diseases associated with abnormal calcium handling. The goal of this study is to examine the effect of Sigma-1R activation on calcium handing, electrophysiological function, contraction and gene expression in genetically caused cardiac arrhythmia. We will use human induced pluripotent stem cell (iPSC) and rodent models to elucidate the molecular mechanism in which Sigma-1R restores cardiac function in inherited long QT syndrome. Preliminary results show that fluvoxamine, an FDA-approved drug, can be used as a Sigma-1R agonist for these diseases. Therefore, our translational study will provide new insight to inform the development of drugs for genetically caused cardiac diseases.